Refractory asthma: mechanisms, targets, and therapy

Trevor, Jennifer; Deshane, Jessy

doi:10.1111/all.12412

Cited by 113 publications

(101 citation statements)

References 103 publications

(115 reference statements)

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“…In response to various signals from inflammatory cells, such as lung macrophages, and in response to activation by pathogens and their associated molecular pattern products (50), the airway epithelium can release GM-CSF, IL-6, IL-8, and other cytokines that initiate and/or amplify inflammation through recruitment of eosinophils and neutrophils (2,19,51). ICSs can repress transcription of genes encoding these proinflammatory cytokines, inhibiting their synthesis and release by the airway epithelium (52,53).…”

Section: Discussionmentioning

confidence: 99%

Cortisol limits selected actions of synthetic glucocorticoids in the airway epithelium

et al. 2018

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Cortisol, a physiologic glucocorticoid (GC), is essential for growth and differentiation of the airway epithelium. Epithelial function influences inflammation in chronic respiratory diseases. Synthetic GCs, including inhaled corticosteroids, exert anti-inflammatory effects in airway epithelium by transactivation of genes and by inhibition of proinflammatory cytokine release. We examined the effect of cortisol on the actions of synthetic GCs in the airway epithelium, demonstrating that cortisol acts like a partial agonist at the GC receptor (GR), limiting GCinduced GR-dependent transcription in the BEAS-2B human bronchial epithelial cell line. Cortisol also limited the inhibition of granulocyte macrophage colony-stimulating factor release by synthetic GCs in TNF-a-activated BEAS-2B cells. The relevance of these findings is supported by observations on tracheal epithelium obtained from mice treated for 5 d with systemic GC, showing limitations in selected GC effects, including inhibition of IL-6. Moreover, gene transactivation by synthetic GCs was compromised by standard air-liquid interface (ALI) growth medium cortisol concentration (1.4 mM) in the ALI-differentiated organotypic culture of primary human airway epithelial cells. These findings suggest that endogenous corticosteroids may limit certain actions of synthetic pharmacological GCs and contribute to GC insensitivity, particularly when corticosteroid levels are elevated by

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Section: Discussionmentioning

confidence: 99%

Cortisol limits selected actions of synthetic glucocorticoids in the airway epithelium

et al. 2018

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“…Patients with neutrophilic BA demonstrate significant activity of IL-17. The disease severity correlates with the level of serum IL-17 [20]. IL-8 affects neutrophil function, [21] while IL-17 attracts neutrophils to the area of inflammation and active infection [22].…”

Section: Cytokine Interaction With Other Cellsmentioning

confidence: 99%

“…At the same time, exposure to IL-5 causes the Th2 cells to stimulate eosinophils to form leukotrienes and reactive oxygen species. All this, under normal conditions, is aimed at eliminating the antigen, but in patients leads to obstruction and inflammation [20]. …”

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confidence: 99%

Untitled

2017

JLPRR

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Submit Manuscript | http://medcraveonline.com HT and IHD (comparison group) and 20 were healthy subjects. All patients signed informed consent before the study. The Protocol of the study was passed review and was approved by the local ethics Committee of our University. The presence of IgE was determined to tick and house dust allergens, as well as the combined allergens of grass pollen, trees, weeds and flowers, S. pneumon, H. influenzae, and N. rerflava. The following cytokines were investigated: IL-4, IL-6, IL-10, IL-17, IFNγ, TNFα. All patients were examined during disease exacerbation. The INFP and ATP were determined for each subject. The results of the study of CK levels and CK combinations, the so-called cytokine profile, indicate that they cannot be used for clinical diagnosis, including nosological diagnosis, the assessment of disease severity, and for selecting individual therapy, including anti-cytokine medications.The incredible heterogeneity of bronchial asthma (BA) is becoming more and more clear. More than 30 years ago, in 1977, we pointed out the existence of seven clinical and pathogenetic types of BA in patients, subsequently called the following phenotypes: infection-dependent, atopic, hormonal, neuropsychological, autoimmune, significant adrenergic imbalance, and primary bronchial hyperreactivity [1]. Individual methods of diagnosis and treatment were developed for each of these options, and the results of their testing have been repeatedly published. Subsequently, the phrase "primary bronchial hyperreactivity" was replaced with the idea of exercise-induced BA, peri-menstrual and aspirin-related clinical and pathogenetic types (phenotypes) of BA. The methods of individual diagnosis and treatment continued to improve and their efficacy continued to increase.Inhalation corticosteroids (ICS) are considered to be the most effective in the treatment of BA. However, in 5-10% of patients with BA, comprehensive treatment is ineffective even with the inclusion of ICS [2]. Although the percentage of patients resistant to ICS, is quite low, they make up 50% of the overall cost of treatment for patients with BA [3]. The insufficient treatment efficacy of existing methods for a group of patients with BA is a reason for examining the BA phenotypes and the endotypes that form them. Knowledge of the mechanisms (endotypes) that form the phenotypes creates the prospects for developing new treatment methods, which take into account the individual characteristics of BA in a particular patient. A cluster analysis of two large European cohorts identified two phenotypes. The first refers to patients with early onset allergic BA, while the second comprises mainly women with late onset disease, without atopy, and with a high body mass index [4].Seven parameters were selected to classify the endotypes in patients with BA after the cluster analysis: clinical characteristics, biomarkers, lung physiology, genetics, histopathology, epidemiology, and response to treatment. The following BA endotypes were proposed based o...

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“…11 Asthma: Asthma is described as a chronic obstructive inflammatory disease consisting of a cellular component which results in the inflammation of airways and hyper-responsiveness in response to some direct or indirect stimuli. 12 The symptoms include recurrent episodes of wheezing, breathlessness, chest tightening and coughing, particularly at night or in the early morning.…”

Section: Introductionmentioning

confidence: 99%

Untitled

2017

IJPSR

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Asthma is a chronic obstructive disease of airways affecting bronchi, resulting in bronchoconstriction, tightening of chest and airway inflammation. Asthma remains a disease with clearly unsatisfactory therapeutics. With the mounting evidence in support of asthma being an inflammatory illness, anti-inflammatory agents have now become prerequisite for the long-term management of asthma. Along with anti-inflammatory agents, there is a need to search for other effective therapies to treat every aspect of the disease. The present review gives an insight of various approaches available for the management of asthma. A number of drugs are available with chemical diversity as on date for the treatment of bronchospasmolytic conditions. The different sites or receptor involved in this intervention is adrenoceptor, steroid receptor, phosphodiesterase and many more. The agents such as β-agonist, antihistaminics, anticholinergics and inhalation steroids, only treat symptoms and do not cure the underlying inflammation. On the other hand, adenosine receptor modulators, selective PDE4 inhibitors, leukotriene modifiers and lipoxygenase inhibitors represents other therapeutic interventions with more targeted control by acting on different parts of immune system and the inflammatory processes. A combination of both of these approaches has been found to improve asthma control with a reduced dose of steroids. With many representative agents of each of these potential therapeutic targets, undergoing clinical studies, successful development of novel therapeutic agents in this field, is not remote. There is a need to understand completely about the phenotype of asthmatic patients so that each patient will receive proper therapy.

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Refractory asthma: mechanisms, targets, and therapy

Cited by 113 publications

References 103 publications

Cortisol limits selected actions of synthetic glucocorticoids in the airway epithelium

Cortisol limits selected actions of synthetic glucocorticoids in the airway epithelium

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